Osteoarthritis, which is also called "degenerative joint disease", is the most common rheumatic disease and is characterized by a chronic inflammation of the articulation and a progressive depletion of articular cartilage matrix macromolecules. Together with the cartilage degeneracy, osteophytes (small abnormal body outgrowths) occur and develop on the stripped part of the articular bones. Symptoms of osteoarthritis occur in many people over the age of 65, and women are affected twice as often as men. These symptoms are pain, swelling and stiffness of the articulation. In a further stage of the disease, movement of articulations is limited and becomes painfil.
The most commonly used drugs for the treatment of osteoarthritis are the nonsteroidal anti-inflammatory agents (NSAID). Even though these drugs have proved effectiveness in relieving the symptoms of osteoarthritis and in decreasing osteoarthritis cartilage catabolism, some of them, like sodium salicylate, have shown inhibiting properties of the proteoglycan synthesis which may jeopardize the cartilage repair process. Other drugs, such as tiaprofenic acid, which do not inhibit the proteoglycan synthesis and have shown in vitro that they are able to decrease osteoarthritis cartilage catabolism, (Jean-Pierre Pelletier et al. The Journal of Rheumatology 1989;16:5, 646-655), have been unable to provide any preventing effect in development of osteoarthritis when administrated to patients suffering from the latter, (Edward C. Huskisson et al. The Journal of Rheumatology 1995; 22:10-1941-1946). Doxycycline, a member of the tetracycline family, was also shown to reduce, in vivo, the severity of osteoarthritis lesions in the dog ACL model while reducing metalloprotease activity, (Yu LP Jr et al. Arthritis Rheum 35:1150-1159, 1992). Recent data suggests that the action of corticosteroids is associated with a reduction in the synthesis of stromelysin-1 by chondrocytes. (see: Pelletier et al., J Arthritis Rheum 37:414-423, 1994; and Pelletier et al., J Lab Invest 72:578-586, 1995).
Accumulating evidence suggests that an important component of the matrix loss process is related to proteolytic enzyme activity which degrades the principal matrix macromolecules such as collagens and proteoglycans (aggrecans). Several matrix metalioproteases including stromelysin, collagenase, and gelatinase are believed to play an important role in matrix degradation. Support for the role of these enzymes in the arthritic process is found in observations showing that these proteases can be synthesized by chondrocytes and are present in increased amounts in pathological cartilage. Another important factor in osteoarthritis is the occurrence of synovial inflammation. There is compelling evidence that soluble inflammatory mediators such as cytokines, interleukin-1 (IL-1) and tumor necrosis factor-.alpha. a (TNF-(.alpha.), are involved in the osteoarthritis process. See for example:
Pelletier JP et al. A textbook of Rheumatology. Twelfih edition. Edited by DJ McCarthy, WJ Koopman. Philadelphia, Lea & Febiger, 1993; PA1 Pelletier JP, et al. J. In, Osteoarthritis, Edition of Rheumatic Disease Clinics of North Ameria. Edited by R W. Moskowitz. Philadelphia, WB Saunders, 1993; PA1 Pelletier JP et al. J. Rheumatol 22:109-114, 1995; and PA1 Lanick JW et al. Kunkel SL. Pharm Res 5:129-139, 1988.
While cytokines and other mediators have been implicated in the core of the synthesis and release of matrix metalloproteases, IL-1 has also shown other deleterious effects on cartilage matrix metabolism. This cytokine, a product not only of mononuclear cells but also of synoviocytes and chondrocytes, has the ability to suppress the synthesis of collagen type II, characteristic of hyaline cartilage, while augmenting the synthesis of collagen type I collagen, characteristic of fibroblast cells (Goldring MB et al., J Clin Invest 30 82:2026-2037, 1988). In addition, IL-1 reduces aggrecan synthesis (Tyler JA. Biochem J 227:869-878, 1985. and Dingle JT et al., Cell Biochem Funct 9:99-102, 1991), the macromolecule largely responsible for the mechanical properties of articular cartilage.
Thus, this cytokine contributes both to reduce anabolic and enhance catabolic activities in affected joints.
A substance having inhibitory effects on the activity of IL-1 was found in conditioned monocyte medium: Arend WP et al., J Immunol 134:3868-3875, 1985, and in the urine of febrile patients : Balavoine JF et al., J Clin Invest 78:1120-1124, 1986. Characterizations of this molecule has revealed a 22 Kd protein and a specific competitive inhibitor of IL-1 known as IL-1 receptor antagonist or IL-Ira: Carter DB et al., Nature 344:633-638, 1990; and Hannum CH et al., Nature 343:336-340, 1990. This antagonist protein is a product of several cell types including monocytes, synoviocytes and chondrocytes and acts as a competitive inhibitor of IL-1 at the receptor level. In addition, IL 1ra binds with a greater affinity to the type 1 as compared to the type II IL-1 receptor. It has been shown that IL-1ra is capable of blocking some of the effects of IL-1, including the induction of matrix metalloproteins, nitric oxide, PGE.sub.2 synthesis, as well as the expression of other cytokines (Smith RJ et al., Adv Immunol 54:167-227, 1993; Arend VP etal., J Clin Invest 85:1694-1697, 1990; and Evens CH et al. Receptor 4:9-15, 1994). Most of the above mentionned studies have demonstrated a relative deficit in the synthesis of IL-1ra vis-a-vis IL-1 in osteoarthritis and rheumatoid arthritis (RA) synovium.
To date, the majority of the studies exploring the effects of IL-1ra have been in vitro. Its in vivo effects have not been studied yet. Moreover some studies carried out in vivo have failed to demonstrate a therapeutic potential for rhIL-1ra in the treatment of arthritis. For instance, Arner, et al in J Rheum 22:1338-1346, 1995, reported that rhIL-1ra administrated intravenously fails to inhibit cartilage proteoglycan breakdown in polycation induced arthritis in the rabbit. Similarly it has been reported that intraperitoneal injections of rhIL-1ra does not affect the pathogenesis of antigen induced arthritis in mice (Wooley, et al, Arthritis Rheum. 36:1305-1314, 1993).
While the before mentioned drugs have met with limited success in the preventative treatment of osteoarthritis, new and improved method and pharmaceutical compositions are constantly being sought which may effectively reduce the progression of lesion and cartilage degradation in a mammal suffering from osteoarthritis. It is to such a method and a composition that the present invention is directed.
Surprisingly, the inventors have found that the periodic administration to a mammal of a composition comprising an amount of human recombinant Interleukin-1 receptor antagonist (rhIL-1ra) is effective for reducing the progression of lesions and cartilage degradation in a mammal suffering of osteoarthritis.